Pregnancy in the Sickle Cell Disease and Fetomaternal Outcomes in Different Sickle cell Genotypes: A Systematic Review and Meta-Analysis

Background Pregnancy is a major concern among women with the sickle cell disease (SCD), and it is associated with increased adverse outcomes. The aim of the present meta-analysis is to report the fetomaternal outcomes in different sickle cell genotypes. Methods In this systematic review and meta-analysis, a comprehensive search of databases and search engines such as PubMed, Scopus, Web of Science, ProQuest, Cochrane Library, Science Direct and Google Scholar were performed. Any observational studies that had compared at least one outcome such as maternal outcomes, fetal outcomes, and morbidity between two groups of pregnant women with different types of sickle cell genotypes and pregnant women without SCD were evaluated. Results A total number of 9,827 pregnant women with SCD were examined. The results showed that pregnancy in SCD increased the risk of adverse outcomes for the mothers (including postpartum hemorrhage, prematurity, pregnancy-induced hypertension, pre-eclampsia, eclampsia, cesarean section, lower segment cesareansection, maternal death), fetus (including live births, low birth weight, intrauterine growth restriction, APGAR score at 5 min <7, stillbirth, neonatal death, perinatal mortality, acute fetal distress, intrauterine fetal death) and morbidity among the SCD(severe anemia, urinary tract infection, blood transfusion, painful crisis, acute chest syndrome, vaso-occlusive crises). Conclusion According to the results of this meta-analysis, pregnancy in the SCD is associated with an increased risk of maternal outcomes, fetal outcomes, and morbidity among SCD patients with different genotypes. Pregnancy in sickle cell hemoglobinopathies needs careful multidisciplinary management and cautious caring so as to decrease maternal and fetal morbidity and mortality.


INTRODUCTION
Sickle cell disease (SCD), caused by a mutation in the β-globin gene HBB, is the most inherited condition and is common in South African Sahara desert, South America, Central America, Saudi Arabia, India and Mediterranean countries (1). The predominant genotypes that give rise to SCD include Hb SS, Hb SC, Hb Sβ+-thalassemia and Hb Sβ0-thalassemia. Other rare forms include hemoglobin SD and hemoglobin SE (2). SCD is perceived as a global threat by World Health Organization (WHO) and about 5% of the world population and more than 7% of pregnant women worldwide suffer from hemoglobinopathies such as SCD (2)(3). The adverse effects of this disease are serious infections, damage to vital body organs, brain stroke, renal disease, respiratory problems, bone marrow suppression, failure to thrive (FTT), cognitive disorder, delayed maturation in children and the high rate of maternal and fetal mortalities (3)(4).
Many studies have shown that SCD is negatively associated with maternal health and prenatal conditions. The fetomaternal consequences of SCD are complicated. The main maternal complications of pregnancies complicated by SCD anemia, infection, vasoocclusive crisis, preeclampsia, preterm labor and the higher risk of the cesarean. The fetal problems that can affect perinatal outcomes are intrauterine growth restriction, premature birth, abnormal fetal heart rate and intrauterine fetal death. A high rate of maternal and fetal death has been reported in pregnant women with SCD than the healthy population (4-6). As already explained, this disease is accompanied by lifelong adverse effects and preterm mortality. Thus, a higher quality of taking care of people with SCD can improve survival and, thus, the number of fertile women (5). It has been previously shown that SCD can increase complications during pregnancy and in turn negatively influence pregnancy outcomes. However, the inherent heterogeneity of SCD pathophysiology in adjusting these studies can reduce trust in estimating the pregnancy risks of this disease (6)(7). Insufficient information about the outcomes of this disease, with different genotypes, among pregnant women poses challenges in prenatal consultations and developing guideline recommendations based on the available evidence to provide comprehensive prenatal care services. Thus, the present systematic review and meta-analysis helps to explore the maternal and fetal outcomes of different genotypes of SCD taking into account the factors that might cause heterogeneity in the existing body of research evidence.

METHODS
The present study was conducted based on the preferred reporting items for systematic review and meta-analysis (PRISMA) checklist (8), but was not registered in the international prospective register of systematic reviews (PROSPERO) database and a public protocol does not exist. No ethical approval was sought for this systematic review. As this study is a systematic review of previously published studies, the need for ethics approval and patient informed consent was therefore waived. The components of structured question (PICO) were population (P): pregnant women with different types of sickle cell genotypes; and intervention (I): not required; comparison (C): with healthy pregnant women with HbAA; outcome (O): maternal outcomes, fetal outcomes, and morbidity in the SCD.

Eligibility criteria:
Any historical cohort, prospective cohort, retrospective cross-sectional, and retrospective case-control, observational casecontrol, descriptive studies with two comparators and descriptive cross-sectional studies, that had compared at least one outcome such as (maternal outcomes, fetal outcomes, and morbidity in the SCD) between two groups of pregnant women with different types of sickle cell genotypes and pregnant women without SCD were included in this systematic review and meta-analysis. Clinical trials, quasi-experimental studies, reviews, letter to editors, or case reports or those reporting outcomes in only one group or in non-pregnant women were excluded from this systematic review and meta-analysis.
Selection procedure: EndNote X8 software was used to manage the included studies. Out of a total number of 3266 search, 450 texts were excluded due to duplication. Then, the titles of 2,816 texts were reviewed and 1,707 texts that were not related to the topic were excluded. The abstracts of 1,109 texts were reviewed and 900 texts that were not related to the aims were excluded. The full text of 209 studies was reviewed by two researchers (M.A & A.P) based on the inclusion and exclusion criteria. 148 studies were excluded due to the lack of a detailed reporting of findings in the two comparison groups; 4 were excluded due to the report of findings in non-pregnant women; 3 studies were excluded as they were systematic reviews, and 7 studies were so due to the use of randomization clinical trials. Finally, 47 studies were selected and they entered the quality evaluation stage (Figure 1).

Figure 1: Flow diagram of the study
Quality assessment: The Joanna Briggs Institute (JBI) Critical Appraisal 5-item Checklist was used for quality assessment of included studies (casecontrol studies and longitudinal cohort, or cross-each item, "Yes" had a score of 2, "Unclear" 1 and "No" had no score. The total scores of each study were considered as total scores. Quality classification of studies in this 5-item checklist was high (7-10), Moderate (3)(4)(5)(6), and Weak (3>). Figure 2 shows a review of the biases of the reported studies. If there was any disagreements between two authors, it was resolved by consultation with the third author.
Data extraction: The data extraction was carried out independently by 2 authors (M.A. and A.P.) using a standard extraction form. The following information was extracted from each study: authors' names; year of publication; title; design; setting; the number of women in exposed and comparator groups; genotype; and outcomes. For each study, the required data were retrieved for the meta-analysis on the outcomes of interest: maternal outcomes such as premature rupture of membranes (PROM), postpartum hemorrhage (PPH), prematurity, pregnancy-induced hypertension (PIH), pre-eclampsia, eclampsia, gestational diabetes mellitus, cesarean section, lower segment caesarean section (LSCS), maternal death) and fetal outcomes. including (mean birth weight, live births, low birth weight (LBW), intrauterine growth restriction (IUGR).
APGAR score at 5 min <7, stillbirth, neonatal death, perinatal mortality, acute fetal distress (AFD), intra-uterine fetal death (IUFD), and morbidity among the SCD including (severe anemia, urinary tract infection (UTI), blood transfusion (BT), painful crisis, acute chest syndrome, vaso occlusive crises (VOC) were collected for each study. We obtained the gross national income per capita for each study from the World Bank data. Data synthesis and statistical analysis: The analyses were pregnancy based. The main measure of the effect of maternal SCD on fetomaternal and pregnancy outcome was the unadjusted risk ratio, calculated from the given numbers of pregnancies and events. Separate comparisons were made for women with the total SCD, SCT, HbSS, HbSC. In each analysis, the reference group was women with SCT, HbAA, HbSC. If the number of studies in each comparison was at least 3, the analysis was done. Depending on the outcome under consideration, studies with no events in either arm were excluded. The pooled risk ratio was reported with 95% of confidence interval (95% CI). Besides, the randomized model was reported by 95% CI. A pvalue < 0.05 was considered statistically significant. The Q statistic and the I 2 index were used to assess the heterogeneity of the studies. The I 2 index was used due to its accuracy to compensate for the lack of power (the Q statistic) in small sample sizes or increase the power in large sample sizes. In the I 2 index, a value below50% indicated a low variance in the studies. Moreover, a fixed effect model and the inverse variance method were used. Otherwise, instrumental variable (IV) heterogeneity method was used (10). Where substantial heterogeneity existed (by I 2 ), mixed-effects analysis was used to test the study differences using the following variables: quality of study reporting; country gross national income (GNI), and the year of publication. The results are summarized as odds ratios. All statistical analyses were done in the Comprehensive Meta-analysis (version 2) and Rev-Man (version 5.3). The other information about the selected studies is listed in Table 1.    Table 2.

Association between SCD and fetal outcome:
The decrease of live births was statistically significant in pregnant women with SCD vs. HbAA based on 5 studies (RR: 0.8, 95% CI: 0.7, 0.9) and HbSS vs. HbAA based on 5 studies (RR: 0.7, 95% CI: 0.7, 0.9). The increased risk of LBW was statistically significant in pregnant women with SCD vs. HbAA based on 11 studies (RR: 2.  Table 3.  Table 4. Mixed-effects analysis: The mixed-effects analysis demonstrated that the year of publication, quality of study reporting, and GNI comprised the heterogeneity factors in comparing HbSS and HbAA groups for the outcomes of prematurity, PIH, LSCS, UTI, BT, in comparing SCD vs. HbAA for the cesarean section, live births, LBW, IUFD, BT), comparing SCD vs. SCT groups for the cesarean section, in (SCT vs HbAA) for (LSCS), and comparing HbSS vs HbSC groups for LBW. Also, the year of publication, and quality of reporting were found as the The year of publication of the study and GNI were found as the heterogeneity factors in comparing HbSS vs. HbAA for perinatal mortality. Also the quality of reporting the results reporting) was a heterogeneity factor for the outcome (IUGR) in comparing SCT vs. HbAA and SCD-SCT, and also for the BT outcome in comparing SCT vs. HbAA. The detailed effect of these factors on the study results is reported in Table 5. Publication bias assessment:In the present study, publication bias was estimated via the Egger test and the results are shown in Table 3-5.
The graphical funnel plots were symmetrical in most zones and did not reveal any bias.

DISCUSSION
This systematic review and meta-analysis showed that pregnancy in SCD increased the risk of adverse outcomes for the mother (including PPH, prematurity, PIH, pre-eclampsia, eclampsia, cesarean section, LSCS, maternal death), and for the fetus (live births, LBW, IUGR, APGAR score at 5 min <7, stillbirth, neonatal death, perinatal mortality, AFD, IUFD) and morbidity among patients with the SCD (severe anemia, UTI, BT, painful crisis, acute chest syndrome, VOC  (6). In the present study, the mixed-effects analysis showed that in studies in lower-middle income group, the HbSS vs. HbAA genotype was associated with increased RRs in prematurity, PIH, LSCS, perinatal mortality, and UTI, and that HbAS vs. HbAA was associated with increased RRs in PIH and that SCD vs. HbAA was associated with increased RRs in PPH. Also, SCD vs. SCT genotype was associated with increased RRs in the cesarean section. In the studies in high income group, the HbSS vs. HbAA genotype and SCD vs. HbAA were associated with increased RRs in LBW, BT and HbSS vs. HbSC was associated with increased RRs in LBW. Despite the current developments OSD caring and management, as well as obstetrics, and neonatal medicine, there is still a close association between pregnancy complications and morbidity comorbidity and the increased risk of adverse fetomaternal outcomes [6]. Contrary to the existing developments in health care, especially in taking care of pregnant women over the past 4 decades, the maternal and fetal morbidity and mortality rate is high. The therapeutic interventions to improve pregnancyrelated outcomes are restricted in women with SCD, particularly in those with the HbSS genotype (57).
In the present study, the mixed-effects analysis showed that in studies published in 2015 or later, the HbSS vs. HbAA genotype was associated with the increased RRs in prematurity, PIH, LSCS, perinatal mortality and UTI. The SCD vs. HbAA genotype was associated with increased RRs in PPH, cesarean section and LBW). The SCD vs. SCT genotype was associated with increased RRs in the cesarean section. The HbAS vs. HbAA genotype was associated with increased RRs in LSCS. In the studies published before 2015, the SCD vs. HbAA genotype was associated with increased RRs in eclampsia, IUFD, and BT. The HbSS vs.
HbSC genotype was associated with increased RRs in LBW. The HbSS vs. HbAA genotype was associated with increased RRs in BT and the HbAS vs. HbAA genotype. Totally, the adverse outcomes in pregnancy were worse and more prevalent in pregnant women with SCD vs. those without SCD. This study reports that pregnancy complications are more frequent in HbSS than other genotypes. These findings are matched with the reports of several studies (6,15,57,58). The outcomes of pregnancy in the HbSS genotype were worse than HbAA and HbAS. Also, fetomaternal outcomes were worse in HbAS when compared with HbAA. The decreased risk of adverse pregnancy outcome in women with HbSC is matched with the manner of the HbSC genotype. This genotype is frequently benign and may not be recognized until later in adult life (15). The results of a study in Brazil indicated that in women with SCD, the HbSS genotype was associated with a higher frequency of blood transfusion. Also, Sβ-thalassemia was associated with a higher frequency of postpartum adverse events (59). In this study, HbSC women had better pregnancy outcomes. However, the incidence of sickle cell-related complications did not differ between women with the HbSS and HbSC genotype. Therefore, it is not yet possible to predict SC patients who may develop severe complications in pregnancy and it is an acceptable practice to assess all pregnancies in SCD expecting a baby in the hospital. However, Malinowski et al. suggested that early identification of women with SCD at high risk of maternal and fetal pregnancy adverse outcomes can be predicted using routine clinical and laboratory data (60). There are some limitations of this systematic review which should be noted. First, this systematic review was not registered on prospective registration systems for systematic reviews. Prospective registration could improve the quality of a systematic review and increase confidence in the findings. However our results were reported according PRISMA statement in order to minimize possible bias. Second, we did not searched the grey literatures and may could not identify any unpublished research. Like with any systematic review, there is always the risk of publication bias as studies with negative results are usually not published.
According to the results of this metaanalysis, pregnancy in the SCD is associated with an increased risk of maternal outcomes, fetal outcomes, and morbidity among patients with the SCD.
This condition requires careful multidisciplinary management and cautious caring so as to decrease maternal and fetal morbidity and mortality. Therefore, accurate and timely follow-up and monitoring of these pregnancies with a multidisciplinary team comprised of a hematologist, an obstetrician, and a pediatrician is essential. Raising patients' awareness and educating them through communication sessions and a timely screening of complications for women with the SCD are essential to decrease the associated risks.